Towards a Unifying Transcriptional Mechanism for Autism

Autism prevalence is on the rise and we need to understand why. In a study recently published in Nature (article, news release), we found that topoisomerase inhibitors reduce the expression of long genes in mouse and human neurons, including a remarkable number of genes implicated in Autism Spectrum Disorders. This discovery has the potential to explain why numerous transcription regulators are linked to autism and could uncover environmental contributions to autism, topics our lab is actively pursuing.

Unsilencing Angelman Syndrome

Angelman syndrome is a severe disorder with symptoms that include speech impairment, intellectual disability and seizures. This lifelong disorder profoundly impacts patients and their families, yet no effective treatment currently exists. It is well established that this disorder is caused by genetic alterations in the maternally-inherited copy of a gene called Ube3a.

In collaboration with Drs. Ben Philpot and Bryan Roth, we found that topoisomerase inhibitors unsilence a dormant but functional copy of Ube3a in mice. We aim to advance our understanding of how these drugs work, with the ultimate goal of developing treatments for this debilitating, lifelong disorder.

Molecules and Mechanisms for Pain

Chronic pain is a major medical issue, affecting more Americans than heart disease, diabetes and cancer combined (American Pain Foundation). In our laboratory, we are developing new approaches to treat chronic pain. In addition, we study the neural circuits that transmit pain-producing stimuli using molecular, genetic, electrophysiological and behavioral approaches.

We recently found that Prostatic Acid Phosphatase (PAP, also know as ACPP) is expressed in nociceptive (pain-sensing) neurons and functions as an ectonucleotidase, converting adenosine monophosphate (AMP) to adenosine. The released adenosine potently suppresses inflammatory pain and neuropathic pain by acting through A1 adenosine receptors.

Our studies suggest it might be possible to treat chronic pain using recombinant PAP protein or small-molecules that mimic the effects of PAP.

Neural circuit-based approaches.

In mammals, pain signals are transmitted from the periphery to the CNS by two neural circuits; the so called peptidergic and non-peptidergic circuits (Fig. 1). Peptidergic neurons contain neuropeptides, like CGRP, while non-peptidergic neurons bind the lectin IB4.

We recently found a G protein-coupled receptor (GPCR) called Mrgprd which is expressed in a majority of all non-peptidergic neurons. Mrgprd is not expressed in CGRP+ neurons, nor is it expressed anywhere else in the brain or body.

To identify the tissues that Mrgprd-expressing neurons innervate, we engineered knock-in mice that express a membrane-tethered version of enhanced Green Fluorescent Protein (EGFPf) from the Mrgprd locus (MrgprdΔEGFPf). Surprisingly, we found that Mrgprd-expressing neurons only innervate the epidermis of the skin (Fig. 2). Joints and internal organs were not innervated, suggesting pain signals are transmitted from these tissues by molecularly-distinct circuits.

In addition to molecular differences, Mrgprd-expressing axons and CGRP+ axons terminate within different zones of the epidermis (Fig. 2). Mrgprd-expressing axons (green) also terminate beneath the red-labeled CGRP lamina in the dorsal spinal cord (Fig. 3). Taken together, these findings suggest peptidergic and non-peptidergic neurons might have unique functions and connectivity.

Although studied for over 20 years, it is still not known why mammals have peptidergic and non-peptidergic circuits, both of which respond to noxious stimuli. Do these two molecularly different circuits have redundant or non-redundant functions in nociception? In our laboratory, we are trying to answer this fundamental question using a variety of approaches. As an example, we are making and studying circuit knockout mice. These mice are specifically missing either peptidergic or non-peptidergic neurons. We are studying the consequences of these ablations using molecular, electrophysiological and behavioral methodologies. We are also using Channelrhodopsin-2 (ChR2), a light-gated ion channel, to better understand how these circuits interface with pain-related regions of the central nervous system.